Abstract
BackgroundThe pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. MicroRNAs are potential candidates involved in simultaneously coordinating multiple genes under such multifactorial conditions.Methods and resultsMiR-138-5p is overexpressed in pulmonary arterial smooth muscle cells (PASMCs) from PAH patients and in lungs from rats with monocrotaline-induced pulmonary hypertension (MCT-PH). MiR-138-5p is predicted to regulate the expression of the potassium channel KCNK3, whose loss is associated with the development and progression of PAH. We hypothesized that, in vivo, miR-138-5p inhibition would restore KCNK3 lung expression and subsequently alleviate PAH.Nebulization-based delivery of anti-miR-138-5p to rats with established MCT-PH significantly reduced the right ventricular systolic pressure and significantly improved the pulmonary arterial acceleration time (PAAT). These haemodynamic improvements were related to decrease pulmonary vascular remodelling, lung inflammation and pulmonary vascular cell proliferation in situ. In vivo inhibition of miR-138-5p restored KCNK3 mRNA expression and SLC45A3 protein expression in the lungs.ConclusionsWe confirmed that in vivo inhibition of miR-138-5p reduces the development of PH in experimental MCT-PH. The possible curative mechanisms involve at least the normalization of lung KCNK3 as well as SLC45A3 expression.
Highlights
The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways
MiR-138-5p expression is increased in the lungs of MCTexposed rats In 2011, Courboulin et al found that miR-138-5p is overexpressed in the lungs and pulmonary arteries (PAs) isolated from idiopathic PAH (iPAH) patients compared to those isolated from non-PAH patients, and it is overexpressed in the lungs of rats with MCT-Pulmonary hypertension (PH) [6]
We confirmed that miR-138-5p expression was increased in the lungs of rats with monocrotaline-induced pulmonary hypertension (MCT-PH) (Fig. 1a, left panel), while miR138-5p expression was unchanged in the right and left ventricles (RV and left ventricular (LV)) of the same rats with MCT-PH (Fig. 1a middle and right panel)
Summary
The pathogenesis of pulmonary arterial hypertension (PAH) involves many signalling pathways. In PAH, the dysregulation of several miRNAs is involved in the aberrant proliferation of PASMCs and dysfunction of PAECs [3, 4]. Liu J-J et al recently reported that miR138-5p promotes proliferation and suppresses mitochondrial depolarization in human PASMCs by reducing KCNK3 expression [8]. The in vivo inhibition of miR138-5p was found to reduce the development of severe experimental PAH by restoring the expression of the lung mitochondrial calcium uniporter (MCU) complex (MCUC) [17]. We hypothesized that the in vivo inhibition of miR-138-5p reduces the development of experimental PH, partly by restoring the expression and function of KCNK3 in the lungs
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